tbuckley/cabot-search huggingface dataset:
Safety and clinical activity of MEDI5752, a PD-1/CTLA-4 bispecific checkpoint inhibitor, as monotherapy in patients (pts) with advanced renal cell carcinoma (RCC): Preliminary results from an FTIH trial.
Authors: Laurence Albiges, Laura Medina Rodriguez, Sang-We Kim, Seock-Ah Im, Enric Carcereny, Sun Young Rha, Ben Tran, Julio Oliveira, Pablo Maroto-Rey, Wu-Chou Su, Mark Voskoboynik, Alejo Rodriguez-Vida, Luis Costa, Paolo Antonio Ascierto, Maria Amelia Insa Molla, Yi Wang, Shelby D. Gainer, Deepa S Subramaniam, Martin H Voss
Journal: Journal of Clinical Oncology (2022)

107 Background: MEDI5752 is a monovalent bispecific antibody targeting PD-1 and CTLA-4. A phase I, open-label study (NCT03530397) of MEDI5752 monotherapy 2.25–2500 mg IV Q3W showed encouraging antitumor activity in advanced solid tumors. Maximum tolerated dose was not reached; doses &lt;1500 mg were better tolerated than doses ≥1500 mg. Here we present preliminary results in pts with advanced RCC in the escalation (ESC) and expansion (EXP) cohorts. Methods: Eligible pts were ≥18 yrs old (ECOG PS 0–1). In ESC and EXP, pts could be treatment-naïve (1L) or refractory. Eligible EXP pts had clear cell component (ccRCC), were immunotherapy-naïve (IO-naïve) and limited to ≤2 prior lines of therapy. Pts were treated until progression or unacceptable toxicity. Primary objectives were safety and tolerability (ESC), and antitumor activity by objective response per RECIST v1.1 (EXP). Results: Overall, 46 RCC pts were treated: 19 ESC, 27 EXP. In ESC, pts (all IO-naïve, 73.7% prior nephrectomy, 26.3% 1L, 89.5% clear cell histology) were treated across 3 dose levels: 750 mg (n=1), 2000 mg (n=16) and 2500 mg (n=2). Seven pts (36.8%) had objective responses (all PRs); 4 of these were 1L, including 1 each with papillary and sarcomatoid histology. In EXP, pts (all IO-naïve, 63.0% prior nephrectomy, 48.1% 1L [of whom 69.2% had IMDC intermediate/poor risk], 96.3% clear cell histology) received MEDI5752 1500 mg IV Q3W. Ten (38.5%) had objective responses (2 CRs, 8 PRs). In 1L EXP pts, 58.3% had objective responses (1 CR and 6 PRs); disease control rate (DCR) was 91.7% (Table). Grade 3/4 treatment-related adverse events (TRAEs) were seen in 68.4% of ESC and 74.1% of EXP pts. In EXP, treatment-emergent AEs (TEAEs), particularly hepatotoxicity, were the most common cause of treatment discontinuation (D/C). At a median duration of follow-up of 14.6 mo, median duration of response (DOR; including in those who discontinued MEDI5752 due to AEs), median PFS and OS were NR in 1L EXP pts. Conclusions: MEDI5752 monotherapy showed deep and durable antitumor activity in pts with advanced RCC, despite high rates of treatment D/C, particularly in the 1L setting. To better characterize the risk-benefit profile, MEDI5752 is now being explored at doses &lt;1500 mg in 1L ccRCC expansion cohorts. Clinical trial information: NCT03530397. [Table: see text]
Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial
Authors: Lacey J. Padrón, Deena M. Maurer, Mark H. O’Hara, Eileen M. O’Reilly, Robert A. Wolff, Zev A. Wainberg, Andrew H. Ko, George Fisher, Osama Rahma, Jaclyn P. Lyman, Christopher R. Cabanski, Jia Xin Yu, Shannon M. Pfeiffer, Marko Spasic, Jingying Xu, Pier Federico Gherardini, Joyson Karakunnel, Rosemarie Mick, Cécile Alanio, Katelyn T. Byrne, Travis J. Hollmann, Jonni S. Moore, Derek D. Jones, Marco Tognetti, Richard O. Chen, Xiaodong Yang, Lisa Salvador, E. John Wherry, Ute Dugan, Jill O’Donnell-Tormey, Lisa H. Butterfield, Vanessa M. Hubbard-Lucey, Ramy Ibrahim, Justin Fairchild, Samantha Bucktrout, Theresa M. LaVallee, Robert H. Vonderheide
Journal: Nature Medicine (2022)

Chemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC ( NCT03214250 ). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.7%, P = 0.006 compared to historical 1-year OS of 35%, n = 34) but was not met for sotiga/chemo (48.1%, P = 0.062, n = 36) or sotiga/nivo/chemo (41.3%, P = 0.223, n = 35). Secondary endpoints were progression-free survival, objective response rate, disease control rate, duration of response and safety. Treatment-related adverse event rates were similar across arms. Multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivo/chemo and sotiga/chemo. Survival after nivo/chemo correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after sotiga/chemo correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells. A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials.
Metastasis patterns and racial disparities in gastrointestinal cancers: A SEER database population study 2010–2018.
Authors: Abdul Rahman Al Armashi, Faris Hammad, Dina Elantably, Kanchi Patell, Francisco Somoza-Cano, Anas Al Zubaidi, Keyvan Ravakhah, Akram Alkrekshi
Journal: Journal of Clinical Oncology (2022)

3597 Background: Metastatic disease at the time of diagnosis of gastrointestinal (GI) malignancies is a strong predictor of poor outcomes. Differences in metastatic patterns among Caucasians (C) and African-Americans (AA) needs further elucidation. In this study, we analyzed the patterns of metastasis in C and AA in colorectal cancer (CRC), pancreatic cancer (PC), gastric cancer (GC), and liver cancer (LC). Methods: We identified patients with CRC, PC, GC, and LC from the Surveillance, Epidemiology, and End Results Program (SEER) database from 2010-2018. We obtained metastasis data to lungs, liver, bone, and brain at the time of diagnosis. We calculated the relative risk (RR), confidence interval (CI), and standard error with the use of SPSS software, 28.0 (IBM). Results: The most common metastasis site was the liver being highest at 39% in AA with PC. Brain metastasis was the least common. Significant racial disparities were noted. In CRC, AA had a 35-37% increased risk of metastasis to the liver, lung, or bone. AA had a higher risk of liver metastasis in PC and GC, whereas C had a higher risk of lung metastasis. Table 1 summarizes the data findings. Conclusions: This study illustrates the disparities of metastasis from GI cancers among AA and C. While a delay in screening, earlier onset of CRC in AA and socioeconomic factors may explain the disparities witnessed in CRC. However, these factors will fail to explain the difference in metastasis pattern in PC and GC in that AA had a higher risk of liver metastasis, and C had a higher risk of lung metastasis. Moreover, In GC, the brain metastasis rate in C was double that of AA. Further studies of possible biological and other risk factors are needed. [Table: see text]
Machine learning modeling of real-world primary resistance and hyperprogression in immune checkpoint inhibitor (ICI) treated advanced non-small cell lung cancer (aNSCLC) patients.
Authors: Rahul K Das, Deep K Hathi
Journal: Journal of Clinical Oncology (2022)

e21127 Background: Many ICI-eligible patients display primary resistance (1 0 -res), with some experiencing hyperprogressive disease (HPD). Machine learning (ML) on real-world data (RWD) can improve our clinical and mechanistic understanding related to ICI response. Methods: XGBoost models were built on ConcertAI’s oncology clinicogenomic database, comprising structured EMR, curated records from unstructured documents, and NGS reports, to predict 1 0 -res and HPD in aNSCLC patients treated with ICI or chemotherapy (CT) within their 1 st three lines between January 2015 and June 2021. HPD was defined as either tumor progression, treatment (Tx) discontinuation, or death within 49 days from Tx start (index date). 1 0 -res was defined as any of these events after 49 days but within 180 days from Tx start. Models were trained on a clinical (N = 7647, ICI = 3265, 1 0 -res = 3909, HPD = 2076), and a clinicogenomic (CG) (2304, 1271, 1084, 596) cohort. A 60:20:20 split was used for training, validation, and testing. Baseline period was defined as 180 days prior to the index date. Prognostic and predictive factors were identified from Shapley Additive Explanation (SHAP) values. Results: The clinical model was superior at predicting HPD; the CG model was better at predicting 1 0 -res (AUROC = 0.67 for both). Total metastases (≥ 2) and lower levels of hemoglobin (HGB), and lymphocytes, higher ALP were risk factors for both HPD and 1 0 -res. Elevated WBC and bilirubin, higher heart rate, lower body temperature, and history of anti-inflammatory medications were risk factors for HPD. Non-ICI-based regimens, low TMB, lower PD-L1 expression, and mutations in EGFR or KEAP1 were risk factors for 1 0 -res. Mutation in KRAS was protective of 1 0 -res. In addition to PD-L1 and TMB, the models identified prior lung radiation, smokers, higher baseline comorbidities, and positive MMR status as predictive of lower risk of 1 0 -res from ICI but not in CT. STK11 mutation was predictive of higher risk of 1 0 -res from ICI vs. CT. Non-adenocarcinoma histology was predictive of higher risk of HPD from ICI vs. CT. Conclusions: ML on RWD generated evidence to support both established and emerging prognostic and predictive markers for ICI response.[Table: see text]
Outcomes of first-line immune checkpoint inhibitors with or without chemotherapy according to KRAS mutational status and PD-L1 expression in patients with advanced NSCLC: FDA pooled analysis.
Authors: Erica C. Nakajima, Yi Ren, Jonathon Joseph Vallejo, Oladimeji Akinboro, Pallavi Shruti Mishra-Kalyani, Erin A. Larkins, Nicole Lauren Drezner, Shenghui Tang, Richard Pazdur, Julia A. Beaver, Harpreet Singh
Journal: Journal of Clinical Oncology (2022)

9001 Background: While existing data suggest a detriment of immune checkpoint inhibitors (ICI) in other targetable mutations in non-small cell lung cancer (NSCLC), limited retrospective analyses suggest patients with Kirsten rat sarcoma oncogene ( KRAS)-mutated NSCLC benefit from ICI in the front-line (1L). To better define this benefit, pooled data from 12 registrational clinical trials investigating 1L ICI with or without chemotherapy (chemo) in patients with documented KRAS status (mutant or wildtype) was evaluated for efficacy of ICI+chemo, ICI alone, and chemo alone. Methods: Pooled data was evaluated for objective response rate (ORR) and overall survival (OS) by KRAS status (mutant, G12C, or wildtype). ORR and 95% confidence intervals (CI) were estimated using Clopper-Pearson method; median OS was estimated using Kaplan-Meier methods. Subgroup analyses were performed using Cox model stratified by KRAS status and PD-L1 status (Positive (combined positive score (CPS) ≥1), Negative (CPS&lt;1), High (CPS≥50), Low (CPS&lt;50)). Results: KRAS mutational status was reported in 1430 patients (61% wildtype, 39% mutated). KRAS G12C was reported in 11% of patients with a KRAS mutation (157/555). Demographics were similar between KRAS mutated, G12C, and wildtype patients. Amongst all patients, 60% were male, 89% white, 60% positive PD-L1, 67% former or current smokers. Table 1 shows outcomes of chemo+ICI, ICI alone, and chemo alone in each population. Conclusions: This retrospective, pooled analysis suggests that patients with KRAS-mutated NSCLC benefit from 1L chemo-ICI similarly to those with KRAS wild-type NSCLC, and should receive combination therapy upfront. Patients with KRAS-mutated NSCLC derived the greatest benefit from the combination of chemo-ICI as compared to ICI or chemo alone. The small number of patients with documented KRAS G12C mutation limits interpretation of the data for this subgroup. Clinical trials investigating targeted therapies for KRAS-mutated NSCLC in the 1L should include a chemo-ICI comparator arm. [Table: see text]
E2F7/8 is involved in cardiomyocyte polyploidy but does not affect myocardial reperfusion injury recovery
Authors: J Fang, JSA Van Der Geest, B Yao, Q Yang, N Chirico, MA Brans, MT Roefs, P Vader, SCA De Jager, A De Bruin, A Vink, A Van Mil, RM Schiffelers, Z Lei, JPG Sluijter
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): CSC fellowship Background Polyploidy cells consist of more than two complete sets of homologous chromosomes. Although a characteristic feature of cardiomyocytes and observed in all mammalian species, its molecular mechanism and biological functions are still unknown. Cardiomyocytes polyploidy in rodents occurs mainly through incomplete cytokinesis and increases with age. Studies have demonstrated that E2F7/8 transcription factors are key regulators of polyploidy in the liver and pancreas, however, it remains unclear if E2F7/8 control the generation of polyploidy cardiomyocytes and what the functional consequence is post-myocardial infarction (MI). Methods By using a tamoxifen inducible Cre/LoxP approach in new-born mice, we deleted E2F7/8 transcription factors ubiquitously and evaluated the biological significance of postnatal E2F7/8 loss. Mice underwent myocardial ischemia reperfusion injury (IRI) and heart function was assessed by 4D-echocardiography. Cardiomyocyte nucleus polyploidy was measured by FACS and microscope. Results Deficiency of E2F7/8 significantly suppress cardiomyocyte mononucleated and multinucleated polyploidy, as well as dramatically decreased hepatocytes polyploidy. E2F7/8 defect also led to a decrease in cardiac stress related marker lever such as ANP, BNP, MMP2, β-MHC/α-MHC and an increase in CD31 expression level. Surprisingly, E2F7/8 deletion did not have impact on cardiac function and dimensions post-IRI. Conclusion In summary, we identified that E2F7/8 activity is involved in the cellular polyploidy in the heart but did not affect myocardial function after myocardial injury.
Impact of proactive symptom monitoring on quality of life (QoL) and treatment toxicity in patients with cancer receiving chemotherapy: A meta-analysis of randomized clinical trials.
Authors: Faris Tamimi, Sabrina Stajer, Jacqueline Savill, Abhenil Mittal, Consolacion Molto, Massimo Di Iorio, Eitan Amir
Journal: Journal of Clinical Oncology (2022)

1545 Background: Early recognition and management of symptoms can improve outcomes in cancer patients receiving treatment. A number of randomized trials have investigated the effects of adding proactive symptom monitoring to usual care (UC). These include web-based, application-based, or telephone-based assessments. Results have been variable, and the impact of proactive symptom monitoring on QoL, treatment toxicity and utilization of unscheduled acute care remains unclear. Methods: A systematic search of MEDLINE identified prospective, randomized trials that studied the effect of proactive monitoring and intervention versus UC in cancer patients receiving chemotherapy. The difference between proactive symptom monitoring and UC on the mean and SD for QoL using validated scales was collected for each study and pooled in a meta-analysis. Analysis was performed using the standardized mean difference (SMD) using random-effects modeling. The effect size was reported as the Hedges’ adjusted g. We also calculated the odds ratios (OR) for the occurrence of several common symptoms of any grade in the individual trials and pooled them in a meta-analysis. Statistical significance was defined as P &lt; 0.05. Quantitative significance was defined as a difference in QoL score exceeding the minimal clinically important difference (MCID) based on previous studies for each QoL framework. Results: Of the 17 trials which met eligibility criteria, FACT-G and EORTC QLQ C30 were the most consistently utilized QoL tools. The mean difference in score between intervention and control at the last evaluation visits was 2.82 (95% CI -0.57 to 6.21; P = 0.10) in FACT-G and 2.33 (95% CI -0.29 to 4.96; P = 0.08) in EORTC QLQ C30, neither of which met quantitative or statistical significance. There was a statistically significant reduction in fatigue (OR 0.67, 95% CI 0.46 to 0.97; P = 0.04), but no difference in constipation (OR 0.63, 95% CI 0.34 to 1.17; P = 0.15), nausea (OR 1.03, 95% CI 0.72 to 1.47; P = 0.89), pain (OR 0.83, 95% CI 0.62 to 1.10; P = 0.19), or diarrhea (OR 1.41, 95% CI 0.40 to 5.01; P = 0.60). SMD for symptom severity was calculated for fatigue, diarrhea, and nausea. Severity of fatigue was statistically lower with proactive symptom monitoring (SMD -0.45, 95% CI -0.69 to -0.22; I² = 0%, P &lt; 0.001), however, magnitude of effect was modest. Conclusions: Proactive symptom monitoring in cancer patients receiving treatment is not associated with significant or meaningful QoL improvement. Similarly, there is limited impact on individual toxicity.
Community transmission of monkeypox in the United Kingdom, April to May 2022
Authors: Roberto Vivancos, Charlotte Anderson, Paula Blomquist, Sooria Balasegaram, Anita Bell, Louise Bishop, Colin S Brown, Yimmy Chow, Obaghe Edeghere, Isaac Florence, Sarah Logan, Petra Manley, William Crowe, Andrew McAuley, Ananda Giri Shankar, Borja Mora-Peris, Karthik Paranthaman, Mateo Prochazka, Cian Ryan, David Simons, Richard Vipond, Chloe Byers, Nicholas A. Watkins, Will Welfare, Elizabeth Whittaker, Claire Dewsnap, Allegra Wilson, Yvonne Young, Meera Chand, Steven Riley, Susan Hopkins
Journal: Eurosurveillance (2022)

Between 7 and 25 May, 86 monkeypox cases were confirmed in the United Kingdom (UK). Only one case is known to have travelled to a monkeypox virus (MPXV) endemic country. Seventy-nine cases with information were male and 66 reported being gay, bisexual, or other men who have sex with men. This is the first reported sustained MPXV transmission in the UK, with human-to-human transmission through close contacts, including in sexual networks. Improving case ascertainment and onward-transmission preventive measures are ongoing.
Bone metastasis reduces responsiveness to EGFR-TKIs in patients with EGFR-mutated advanced lung adenocarcinoma.
Authors: Kan Jiang, Gen Lin, Xinlong Zheng, Feng Long
Journal: Journal of Clinical Oncology (2022)

e21085 Background: The response of epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitors (TKIs) to bone metastasis site in patients with EGFR mutated lung adenocarcinoma remains to be determined. Methods: This is a retrospective analysis of the efficacy of EGFR-TKIs for lung adenocarcinoma patients with EGFR mutations, comparing patients with bone metastases (BM) and those with no bone metastases (NBM). BM patients need extra imaging to assess the efficacy of bone metastasis sites . Overall response rate (ORR), disease control rate (DCR), median progression-free survival (PFS) and progression patterns were evaluated. Results: Of the 502 patients, 175 were enrolled (BM 96, NBM 79) from January 2012 to December 2017. 125 patients had disease progression on January 31, 2018. The clinical characteristics of the two groups were not significantly difference. The median PFS was 11.0 months in NBM group and 7.0 months in BM group ( P= 0.013) . The median PFS in patients with multiple BM (≥ 4) was significantly lower than that in patients with oligometastases (1-3) and NBM (7.0 months vs 10.0 months vs 11.0 months, P = 0.003). Multivariate analysis confirmed that bone metastasis was an independently negative predictor of PFS for EGFR-TKIs ( P = 0.017). The ORR and DCR of NBM group were higher than those of BM group (70.9% vs 56.3%, P = 0.046 and 96.2% vs 85.4%, P= 0.017). Bone was one of the frequently progressive sites of EGFR-TKIs therapy, accounting for 52 of 125 (41.6%). The incidence of bone progression in NBM patients was significantly lower than that in BM patients(11.8% vs 62.2%, P &lt; 0.001). Conclusions: Bone metastasis, especially multiple bone metastasis, reduces the response to EGFR-TKIs for lung adenocarcinoma with EGFR mutations. Bone metastasis monitoring should be a routine clinical practice for BM patients.
In nonischemic systolic HF, prophylactic ICDs did not reduce all-cause mortality vs. usual care at 10 y
Authors: Maude Sestier, Darryl Leong
Journal: Annals of Internal Medicine (2022)

Source Citation Yafasova A, Butt JH, Elming MB, et al. Long-term follow-up of DANISH (The Danish Study to Assess the Efficacy of ICDs in Patients With Nonischemic Systolic Heart Failure on Mortality). Circulation. 2022;145:427-36. 34882430
Impact of the oral chemotherapy pharmacist on direct cost avoidance and cost savings of oral oncolytics at an integrated health system.
Authors: Analia Nguyen
Journal: Journal of Clinical Oncology (2022)

e18839 Background: The impact of oncology pharmacists on patient care have been well-documented including enhanced medication safety and efficacy, increased medication adherence, improved provider and clinic burden, and increased patient and provider satisfaction. There is a scarcity of articles relating to pharmacists’ drug cost savings or cost avoidance of oncologic drugs in an oral chemotherapy management clinic within an integrated healthcare system. Cost savings and cost avoidance studies are needed to reinforce this practice and gain support and funding from hospital administration. Methods: This retrospective, observational study analyzed interventions made by oncology pharmacists in the Pharmacist-Managed Oral Chemotherapy Clinic at Kaiser Permanente San Diego and determine the direct drug cost savings and cost avoidance effects over one year. Cost savings and cost avoidance were calculated by comparing the costs of drug utilization if no interventions were implemented versus costs of drug saved from accepted interventions for dose reduction, dose delay, temporary dose hold, therapy discontinuation, therapy conversion, formulary alternative conversion, and brand to generic conversion. Secondary outcomes included the highest and average cost avoidance per intervention, intervention type, medication, medication class, and cancer type. Additionally, interventions that did not lead to direct drug cost savings such as adverse drug reaction management, drug interaction identification, and supportive care recommendation were also recorded. The secondary endpoint was oncologist satisfaction via a six-question satisfaction survey. All documented oncology pharmacist interventions that were made in the Oral Chemotherapy Clinic from January 1 to December 31, 2021 were reviewed for study inclusion. From a report generated monthly from the electronic health record (EHR), retrospective chart review was conducted to verify whether each cost-savings intervention was truly recommended by an oncology pharmacist and if the intervention was accepted by the treating oncologist. The Average Wholesale Price (AWP) of drugs listed on Lexicomp as of November 1, 2021 was used to calculate the drug cost savings and cost avoidance. During this period, there were no changes to practice and no increased efforts to identify interventions. Results: As of September 2021, 156 interventions were identified, with a total cost savings and cost avoidance of $2,245,856. Once all data have been collected for the remainder of 2021, descriptive statistics will be used to analyze and stratify the data as appropriate. Conclusions: Pharmacist interventions in the Oral Chemotherapy Clinic led to significant overall cost savings to the health care system. It is reasonable to expect that higher cost savings will be achieved as more oral chemotherapy agents are managed by pharmacists.